DE2629752A1 - NEW CARBONIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

BOEHRINGER MAHiJHEIM GMBH ^ '2067

Heue Carbonsaearedprivate and method for their ITo rηto llun g

The present invention relates to carbonic acid derivatives general formula I.

/ r \

A V-CO-KH-Y-A Λ-X-COOII (i),

in the

A is a valence line or one of the groups -CH ₂ -, -CH ₂ -CH ₂ -, -CH = ClI-, -0-, -CH ₂ -O-, -S-, -CH ₂ -S-,

V is a straight-chain or branched, saturated or unsaturated trivalent hydrocarbon radical with 1-4 carbon atoms,

and R _{2 can be} identical or different and are hydrogen, hydroxy-y alkyl, alkoxy radicals or halogen,

Hydrogen _f hydroxy <- or one alkoxy group,

• A

709881/046 S-

Y cine optionally branched lower alkylene group with 1-3 carbon atoms,

X is a valence bar, a straight or branched chain, saturated or unsaturated alkylene chain with 1-6 carbon atoms mean

their physiologically harmless salts, esters and amides, "Process for the production of the same, as well as their use for the production of drugs with hypoglycemic and / or hypolipidaemic Effect.

In all cases, “alkyl” and “alkoxy” are to be understood as meaning straight-chain or branched radicals with 1-5 carbon atoms. Preferably find the methyl group in the alkyl radical, "in the Alkoxy radical the methoxy to butoxy group use.

Among trivalent hydrocarbon radicals are preferred the groups

) cil-,) c = CII-, ^ CIi-CII ₂ -,

VH-CH-, WcH ₂ -CH ₂ -, VcII-CH ₂ -,

^C 2 ^H 5

to understand.

Halogen means fluorine, chlorine and bromine.

7.0988 1 / 046S

The new compounds of general formula I and their physiological harmless »salts, esters and amides are surprisingly pronounced hypoglycaemic and / or hypolipidaemic activity.

The compounds of the general formula I can be prepared by processes known to 3xch, preferably by a) an amino-carboxylic acid of the general formula II

H ₂ NY- ^ Vx-COOH (II),

in the

Y, X and E _{3 have} the meanings given above, or their acid derivatives,

with a reactive acid derivative of the acid T-COOH, where T is the trioyclisohe system

of the formula I, in which A, Y ₁ ^- R ₁ and R _{2 have} the meanings given above, or

709881/0465

b) a compound of the general formula III

T-CO-NII-Y-Cv / V-X-B

in the

T, Y, R ₃ and X have the meanings given above and B represents a radical which can be converted into the carboxyl group by oxidation, or is oxidized or

c) in the event that X is a straight-chain or branched, saturated or unsaturated alkylene chain with 1-6 carbon atoms means a compound of the general formula IV

¹ C-CO-NII- TL Vz'-GZ-COOR (iv),

in v / elcher.

T, R ₃ and Y have the meanings listed above, Z and Z ^{1 can be} identical or different and have a valence stroke, a straight-chain or branched, saturated or unsaturated alkylene chain with 1-5 carbon atoms,

R hydrogen or an alkyl group

709881/0466

and G denote the -C group or the -CH group,

Il 1

0 L-

where L represents the hydroxyl group or halogen, reduced, or

d) in the event that X is a straight-chain or branched branch or unsaturated alkylene chain with 2-6 carbon atoms, a compound of the general formula V

T-CO-NII-Y- / V-K-C = O. (V),

in the

T, R ₃ and Υ have the meanings given above, M represent hydrogen or lower alkyl with 1-4 carbon atoms, and K represent a valence stroke or a straight-chain or branched, saturated or unsaturated alkylene with 1-4 carbon atoms,

with a reactive methylene component of the general formula VI

/ COOR '

709881/0465

in the

R ^{1 is} hydrogen, alkali metal, lower alkyl or an acyl group and

Q represents hydrogen, lower alkyl with 1-4 carbon atoms or an activating group such as the nitrile group or one of the radicals -COOR ¹ or -PO (OR) ₂ , in which R 'and R are as defined above,

", the unsaturated compound obtained optionally is subsequently saponified, decarboxylated or hydrogenated, or

e) in the event that X is a straight-chain or branched, saturated or denotes an unsaturated alkylene chain with 1-6 carbon atoms, a derivative of a carboxylic acid of the general formula VlI

(VII),

in the

T, K ₃ and Y have the meanings given above and X ^{1 represents} a radical smaller than X by one methylene group, reacts with diazomethane according to "Arndt-Eistert", or

• A 709881/0 46 p

Γ) in the event that X in the general formula I a straight-chain, saturated alkylene chain with 1-4 carbon atoms represents a ketone of the general formula VIII

T-CO-KH- Y \ , 0-CU (VIII),

in the

T, Ii ₃ and Y have the meanings given above and TJ represents an alkyl group with 1-4 carbon atoms, under the conditions of an optionally modified "Willgerodt-Kindler synthesis", or

g) in the event that X is a straight-chain or branched, saturated or unsaturated -alkylene chain with 2-6 carbon atoms means a halogen compound of the general formula IX

T-CO-NH-Y- /, A-K-CH-HaI (ΐΧ),

in the

T, R ₃ , Y, K and M have the meanings given above and Hal represents a halogen, with a reactive methylene component of the general formula X.

^ COOR ₅
C ^ (X),

• COW
R ₄

709881/0465

whereby " "

K _{4 is} hydrogen or lower alkyl with 1-4 carbon atoms, E _{5 is} lower alkyl, Me is an alkali or alkaline earth metal and W is the radical OE ₅ or the methyl group, converts, saponifies and optionally decarboxylates,

and subsequently, if desired, the compounds of general formula I obtained converted into other compounds of general formula I and a resulting acid derivative of general formula I is optionally converted into the free acid odez ¹ a resulting free acid of general formula I, if desired, esterified, in an amide or in transferred to a physiologically compatible salt.

In process a), the reactive acid derivatives of the acid Ϊ-COOII are mainly acid chlorides, which are commonly used In some cases, e.g. by decomposing the carbonic acid with thionyl chloride, obtained can be. However, their esters, azides, anhydrides or mixed anhydrides can also be used just as well. Such reactive intermediates can also be produced in a one-pot process and implemented further immediately.

The reaction with the intermediate of the general formula II can according to "Schotten-Baumann". Viii one under anhydrous Working conditions are preferably absolute pyridine or another organic solvent such as toluene, Methylene chloride, acetone or dioxane, with the addition of a tertiary amine (such as triaethylamine) is used. Instead of Free amino compounds can also be used their salts.

As Saeurederivate the compounds of general formula II are preferably the esters, especially the methyl and ethyl esters, nitriles, acid anhydrides or Saeurea.mide ± _n question, which then, after the reaction, if appropriate by hydrolysis according to methods known per se into the free carboxylic acids or the humanized derivatives can be transferred.

./.70988 1/0465

In method b) there are ala oxidizable groups B in substances general formula III preferred to hydroxymethyl-, amino-methyl-. Forrayl or acetyl groups or their functional derivatives in question, those with the usual oxidizing agents, such as permanganates or dichromates, in the case of the formyl group also with atmospheric oxygen or silver oxide or in the case of the acetyl group as well can easily be oxidized to the carboxyl group by alkali hypohalite.

The compounds of the general formula III, which are used as starting compounds are used in process b) are new and have as precursors of the compounds of general formula I. also hypoglycemic and / or hypolipidemic effectiveness. They are produced by processes known per se, in particular analogously to process a), where instead of the acid or whose derivative of the general formula II the corresponding compound with the oxidizable group B is used. Of course but conversely, compounds of the general formula I can also be used baw. their acid derivatives such as esters, acid halides and acid amides can be converted into compounds of the general formula III by reduction.

The ketocarboxylic acid derivatives used as starting material in process c) of the general formula IV can be prepared by processes known per se, in particular analogous to processes a), where instead of the acid or its derivative of the general formula II the corresponding derivative / t with the reducible Remainder G is used.

In the event that Z is not equal to Vainzstrich, the ketocarboxylic acid derivatives of the general formula IV used as starting material in process c) can also be prepared, ^{for example after the Claisen 1 ester condensation.}

The compounds of the general formula IV, which are used as starting compounds v / earths used in method o) are new and also have hypoglycemic and / or hypolipidaemic Y / ineffectiveness,

709881/0465.

The reduction of the compounds of general formula IV with G = keto group to prebondings of general formula I can be carried out, for example, with the aid of zinc / hydrochloric acid in the sense of a "Clernmensen reduction" or according to "V / olff - Kishner" with hydrazine / alkali . However, it is preferably carried out catalytically with hydrogen in the presence of noble metals such as palladium or platinum. The preferred solvent in this case is a lower alcohol. You can also work in glacial acetic acid to which a trace of sulfuric or perchloric acid or molar amounts of hydrochloric acid is added. The Eeaktionstemperatur is at 20-6O ⁰ C, the pressure between 1 and 10 at. Viasserstoff.

Compounds of the general formula IV with G = -CH- can be

OK

e.g. by reducing the corresponding keto derivatives. The reduction can be catalytic in the presence of noble metals such as e.g. palladium or platinum. Complex metal hydrides are also used as reducing agents, preferably is Sodium borohydride used. In this case, the reaction can take place in an alcohol, in particular methanol, or in an aqueous-alkaline solution Medium to be carried out. The halogen derivatives can be prepared from the hydroxy compounds by generally known methods. The reduction to compounds of the general formula I can also be carried out by methods known per se, for example, according to the conditions given above (G = keto group).

The implementations according to method d) are under the general known reaction conditions of the "Perkin reaction" or the "Knoevenagel reaction" carried out. The one after the variant "Cope" odor from the carbonyl compound with 2-phosphonoalkanoic acid » Acid derivatives represented by trialkyl esters in the presence of alcoholates are then optionally decarboxylated saponified to acid. Under lower alkyl the substituents R and R ' one understands alkyl groups with 1-5 carbon atoms, especially methyl and ethyl groups. The cinnamic acid derivatives thus produced can then, for example, be catalytically hydrogenated with hydrogen in the presence of palladium or platinum to give the saturated compounds will.

709881 / 04SB

- ^ - 26297S2

Method e) includes the "Arndt-Eistert" method in which a derivative, especially chloride, of a carbomic acid General formula VII converted into a diazoketone with diazomethane will. Exposure to UV light, heat or catalysts such as silver oxide transforms the diazoketone into a carboxylic acid derivative of the general formula I converted.

The ketones of the general formula VIII used in process f) can be produced by processes known per se, in particular analogously to process a), with the acid or its derivative being replaced by the general formula II that the corresponding intermediate with the group -CO-U is used. These intermediates can be easily represented by acylation according to "Friedel-Crafts". The thiomorpholide obtained in the "Willgerodt-Kindler synthesis" is saponified in an alkaline or acidic medium.

Instead of the Sch.wof.els and the secondary amine can be used simultaneously Reduction of the carbonyl group to the methylene residue and oxidation of a methyl group to the carboxyl residue also a thallium (III) salt, preferably thallium (III) nitrate, and perchloric acid used will.

The reaction according to process g) is carried out according to the method known per se of the alkylation of β-dicarbonyl compounds. The subsequent saponification of the ß-diketo compound is preferably carried out with alcoholate according to the conditions of an "ester cleavage" performed. The lower alkyl group of the substituent Eg is understood to mean alkyl groups with 1-5 carbon atoms, in particular Methyl and ethyl.

In the event that R ₁ , Hg and / or R, denote hydroxyl, these substituents must be protected before the reaction by appropriate groups which can be split off.

The subsequent transfer of compounds of the general formula I into other compounds of general formula I is done, for example, by alkylation of the hydroxyl groups in a known manner by reaction the alkali phenolates with dialkyl sulfates or alkyl halides.

709881

Likewise, from alkoxy compounds of the general formula I according to the known methods of ether cleavage (e.g. using hydriodic acid or Lewis acids) hydroxy-substituted compounds of the general formula I can be obtained.

Furthermore, compounds of the general formula I with olefinic double bonds can be carried out in a known manner Hydrogenation with hydrogen in the presence of catalysts into the corresponding saturated compounds of general formula I are converted.

Those occurring as intermediates in the processes listed above Esters can be isolated or, if appropriate, saponified directly to give the corresponding carboxylic acids. Conversely, the obtained carboxylic acids again according to known ones. Methods too the desired esters are implemented.

Saponifications of eoters, nitriles, amides, etc., are preferred carried out in an alkaline medium.

For a possible esterification of the carboxyl group are suitable in principle all alcohols. The lower monohydric alcohols such as methanol, ethanol or propanol and polyhydric alcohols are preferred Alcohols, e.g. glycol, or alcohols with other functional groups such as /, ethanolamine or glycol ethers.

709881 / 04S5

2625752

The amides of the general formula I according to the invention can according to known methods can be prepared from the carboxylic acids or their reactive derivatives by reaction with amines. As amine components are e.g. ammonia, alkylamines, dialkylamines etc. possible? however, amino acids such as p-aminobenzoic acid are preferred Anthranilic acid, phenylalanine, alanine and ß-alanine.

In particular, alkali-j are used as physiologically harmless salts Alkaline earth and ammonium salts, as well as salts with blood sugar lowering effective basic compounds, especially biguanides, in question. These salts are prepared in a manner known per se, for example by reaction with the corresponding free bases or carbonates.

As hypoglycemic and / or antihyperlipidaemic according to the invention Preparations can be any conventional oral and parenteral application forms, for example tablets, capsules, Dragees, syrups, solutions, suspensions, drops, suppositories, etc. For this purpose, the active ingredient is mixed with solid or liquid carriers and then brings them into the desired Shape. Solid carriers are e.g. starch, lactose, mannitol, methyl-. cellulose, talc, highly dispersed silica, higher molecular • Fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, Magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols). For Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners. as The injection medium is preferably water, which the usual additives such as Contains stabilizers, solubilizers and / or buffers. Such additives are e.g. acetate or tartrate buffers, Ethanol, complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic Salae) or high molecular weight Polymers (such as liquid polyethylene oxide) to regulate viscosity.

· / · 709881/0485

For the purposes of the present application, preference is given to those in the the following examples mentioned compounds nooh the following

3- <4- [2- (3- £ fluorenyl- (9) J -propionamido) -aethyl] -pheny1 ^ - propionic acid

4- ^ 2- [3- (fluorenylidene- (9)) -propionamido] -aethyl ^ -benzoic acid

3- ^ 4- [2- (2-chloro-fluorenyl- {9) -acetamido) -aethyl] -phenyl) -propionic acid

3- {4- [2- (3-chloro-6-methyl-fluorenyl- (9) -acetamido) -aethyl] -phenyl-1-propionic acid

3- ^ 4- [2- (6, ll-dihydro-dibenz [b, e] oxepin-ll-carboxamido) -aethyl] · phenyl ^ propionic acid

3- {2-Butoxy-4- [2- (fluorenyl- (9) -acetamido) -aethyl] -phenyl) -propionic acid

3- <4- [2- (2- ^ 6 _f ll-dihydro-dibenz [b, e] oxepinyl- (ll) J -propionamido) -aethylj-phenyl ^ -propionic acid

./. 70988 1/046 p

3- <4- [2- (Pluorenyl- (9) -acetamido) -aethyl] -phenyl> -2,2-dimethylpropionic acid

3- [4- [2- (Pluorenyl- (9) -acetamido) -aethyl] -phenyl) -butyric acid K_ ^ 4_ [2- (piuorenyl- (9) -acetamido) ~ ethyl} -C) enzoyl) -L-alanine

N- £ 3- ^ 4- [2- (fluorenyl- (9) -acetamido) -aethyl] ~ phenyl) -propionyl? · ß-alanine

3- <4- [2- (3-Hydroxy-fluorenyl- (9) -acetamido) -aethyl] -phenyI ^ - propioncaeure

4-C2- (2- [piiorenyl- (9)] -propionamido) -aethyl> -benzoic acid 4- <2- (2- [pluorenyl- (9)] -propionamicLo) -aethyl> -2-mothoxy-benzene

acid

3- <4- [2- (2- [Fluorenyl- (9)] -butyramido) -ethyl] -phenyl> pr op ion säur e

3- <4- [2- (9-Methyl-fluorenyl- (9) -acetamido) -ethyl] -phenyl> propionic acid

3- <4- [2- (4,5-Dimethoxy-fluorenyl- (9) -acetamido) -ethyl] -phenyl> -propionic acid

The following examples show some of the numerous process variants, which can be used for the synthesis of the compounds according to the invention. However, they are not intended to limit the Represent the subject of the invention.

709881/0465

-IA-

example 1

3- <4- [2- (xanthene ~ 9 ~ carboxamido) -aethyl] -phenyl)> ~ propionic acid

To 3.2 g of 3- [4- (2-Aminoaethyl) -pheny-l] -propionßaeureaethylesterhydrochlorid (mp. 165-167 ° C) in 24.5 ml 1 η Batronlauge one adds at 0 ° C a solution of 3, 0 g of xanthene - ^ - carboxylic acid chloride (made from xanthene-9-carboxylic acid and thionyl chloride) in 15 ml of potassium chloride. The mixture is allowed zunaechßt ¹ Z ₂ hours under ice-cooling, Dajon 2 hours at room temperature After stirring, separating the two layers and shake the aqueous layer again with methylene chloride. The combined organic layers are washed successively with dilute sodium hydroxide solution and dilute saline acid, they are dried, the ethylene chloride is evaporated and the residue is recrystallized from ethanol. This gives 4.2 g (= 80 ° fo of theory) 3- <4-f2- (xanthene-9-carboxamido) -aethyllphenyl ^ -propionic acid ethyl ester of p . 144-147 "C

40 g of 3- <ii- [2- (xanthene-9-carboxamido) -aethyl] -phenyl> -propionic acid ethyl ester are heated under reflux for 2 hours with the solution of 1.6 g of sodium hydroxide in 40 ml of ethanol. Then you cool off; the sodium salt of 3- ^ 4- [2 ~ (xanthene-9-carboxomido) ~ ethyl] phenyl ^) propionic acid precipitates out. This is filtered off with suction, washed with a little ethanol, dissolved in water and the solution is acidified. The free carboxylic acid is filtered off and recrystallized from ethanol.
Yield 3.0 g (· = 80.5% of theory)} mp. 180-183 ⁰ C.

One gets in an analogous way

1. by reacting deo 3- [4- (2-aminoethyl) phenyl] propionoaeureaethylester hydrochloride with the corresponding carboxylic acid chlorides the following compounds:

a) 3- <C4- [2- (5n-dibenzo [a, d] cycloheptenyl- (5) -acetamido) -aethyl] -

phenyl> -propion3aourcaethylester ________

Mp. 105-107 ⁰ C (from 80 ^ sodium isopropanol)

709881/0465 V.

- yr -

and from it through Vexßeifen the

5- <4- [2- (dibenzo [a, d] cycloheptenyl- (5) -acetamido) -aethyl] -phenyl ^ -propionic acid

Mp. 174-177 ° C (from 50% strength methanol)

\>) 5- ^ 4- [2- (6, ll-dihydro-dibenzXbiejoxepinyl ^ 11) -acetamido) ·

ethyl] -phenyl> -propionic acid ethyl ester

Mp 88-89 ⁰ C (from 80 5 sodium isopropanol). And therefrom by saponifying

5 "^ 4- [2- (6, ll-dihydro-dibenz £ b, e] oxepinyl- (ll) -acetamido) -ae thyl1-phenyl> -propionic acid

Mp. 124-125 ^O C (from 80% isopropanol)

o) 5- <4- {2- (3-Hethyl-fluorenyl- (9) -acetamido) -aethyl] -phenyl> -

propionsaeureaethyi ester _;

Mp. 90-92 ⁰ C (from methylene chloride)

and from it by verceifen the

5- <4 ~ [2- (j-Mothyl-fluoronyl- (9) -acetamido) -aethyl] -phenyl> propionic acid ; \

Mp. 184-187 ⁰ C (purified via the sodium salt)

d) 5- <4- [2- (fluorenylidene ~ (9) -acetamido) -aethyl j-phenyl) '-

propionsa-eureaethyleoter

Mp. IJO ⁰ C (from methylene chloride)
and from it by saponifying the "

-5- <4- [2- (fluorenylidene- (9) -acetamido) -aethyl] -phenyl> propionic acid ;

Mp. 205-204 ⁰ C (from ethanol)

709S81 / 0465

-VS-

e) 3- <4- £ 2- (fluorenyl- {9) -acetamido) -aethyl] -phenyl> - ' propionic acid ethyl ester

Mp. 122-124 ° C (from methylene chloride)
and from it by saponifying the

3- (4- [2- (Fluorenyl- (9) -acetamido) -aethyl] -phenyl) -propionic acid ~

Mp. 218-219 ° C (from E3sigester)

f) 3_ <4- [2- (2-i-: ethyl-6, ll-aihydro ~ dibenz [b, e] oxepinyl- (ll) -

acetan ido) -R.ethyl ^ - ^ Dhcinyl · V-τ'ro τliongacure-fiethylester (oelif?) and from it by saponification the
3- <4- [2- (2-Kethyl ~ 6, ll-dihydro-dibens [l>, e] oxepinyl- (ll) mp. 174-175 ° C (from ethanol)

3 - <^ 4- [2- (9,10-dihydroanthryl "(9) -acetamido) -aethylj-phenyl ^ -propionic acid ethyl ester

Mp. 138 ~ 139 ° C (from ethanol)
and from it by saponifying the

3- (4 ~ [2 · - (9 »10-Dihydroanthryl- (9) -acetamido) -aethyl] -phenyl ^ -propionic acid

Mp. 190-20O ⁰ C (from ethanol)

709881 / 046S

7th

262975a

3- (4_ [2- (2-i> luorenyl- (9) J-p_opionaLnido) -aethyl} -phenyl> propionic acid ~ ethyl ester (oily)

and from it by saponifying the

3_ ^ 4_ [2- (2-rPluorenyl- (9) J-propionainido) -aethyl] -phenyl]? -

propionic acid

Mp. 159-142 ⁰ C (from isopropanol + 10 ^ water)

2. By "OiUBevzung deu 4- (2-Aminoaethyl) -benzoeBaeureaQtbylester-hydrochloridß (Mp. 195-200 ^o -C) with the corresponding carboxylic acid chlorides the following compounds:

a) 4-T2- (Xanthenyl- (9) -acetamido ^ -acthyll-benzo e naeureaethylester pp. 160-163 ° C (from methylene chloride)

and from it by saponifying the

4-f2- (Xanthenyl- (9) -acetamido) -aethyll-benzoic acid, pp. 256-258 ⁰ C (from ethanol)

* b) 4-r2- (Flv.oren-9-cnrboxamido) -aethyl1-benzo esaeureaethylester mp. 188-191 ° C (from ethylene chloride)

and from it by saponifying the

4-r2- (F3-UorGn-9-oarboxamido) -aethyl] -benzoic acid pp. 250 ⁰ C (purified over the sodium salt)

709881 / 046S

ο) 4- [2- (6, ll-Dihydro-dibenzfb, e] oxepinyl- (ll) -acetamido) -aethylJ- benzoesaexireaethyl ester (oelift)

and from it through Yerseifen die

4- [2- (6, II-I) ihydro-dibenz [b, e] oxepinyl- (II) -acetamido) -aethyl] -benzoic acid. _k

Ip. 178-182 ° C (from ethyl acetate)

d) 4- [2- (10, ll-Mhydro-JH-dibenzofajdjoyciloheptenyl- ^) - acetamido) ·

aethyl] -bonzoeeaeuroaethylenter ■

Mp. 127-150 ⁰ C (also ether)
and then by Yerseifen die

4- [2- (10, II-dihydro-51I-dibenzo [a, d] cycloheptenyl- (5) -acetamido) -ethyl 1-benzoic acid

Ii ¹ P. 2O3-2O6 ° C (from ethanol / water)

e) 4- [2- (2,6-Dinethyl-fluorenyl- (9) -acetamido) -aethyl] -benzoe saevi T'e -ethyl ester

Mp. 145-148 ⁰ C (from toluene)
and from it through Yerseifen die

4- [2- (2,6 -]) imethyl-fluorenyl- (9) -acetamido) -aethyl] -benr.oe sac-ure ■ _

Mp. 224-225 ^o C (from isopropanol)

709881/0485

f) 4- [2- (9,10-I) ihydroanthryl- (9) -acetaraido) -aethyl] -benzoe s acurea c t hy 1 e & ter

Pp. 149-152 ⁰ C (from ethanol)
and from it by saponifying the

4- [2- (9, 10-dikydroanthryl- (9) -acetamido) -aethyl] -ben '/, oe acid

Pp. 239-241 ^o C (from ethanol)

5. by reacting 4- (2-Aininoaethyl) -phcnylessißnaeurGaethylester-hydrochloridß (Γρ. 177-17O ° C) with fluorocnyl- (9) -acetyl chloride the

4- [2- (Pluorenyl- (9) -o.cetamido) -aethyl] -phenyleB3igsaeure Ethyleotcr

Mp. 143 ~ 146 ^O C (from methylene chloride)

and daraiis by saponifying the

4- [2- (Pluorenyl- (9) -acetamido) -aethylj-phenylacetic acid

Mp. 212-214 ° C (from isopropanol)

4. by reacting the 2- [4 ~ (2-Aminoaethyl) -phenyl] - 'butterBacure · aethyleoter-hydrochlorids (oily) with fluorenyl- (9) -ß-cetylchloride the

2- <4- [2- (Fluorenyl- (9) -acetamido) -aethyl] -phenyl>-t> utter aaeureaothylcster (vachnartip;)

· ^Α 709881 / (Κ85

and from it by saponifying the
2- <4- £ 2- (fluorenyl- (9) -acetaraido) -aethyl] -phenyl) -butyric acid

Γρ. 88-90 ⁰ C (from xylene)

5. by reaction of 3- [4 ~ (aminomethyl) ~ phonyl] ~ propionBaeureaethyleater-hydrochloride (Mp. 192-193 ° C) with fluorenyl (9) acetyl chloride the

3- [4 ~ (1.'luorenyl- (9) -acetamido-methyl) -phenyl J-propionic acid-

aethyloster -

Mp. 155-156 ^O C (from isopropanol)

and from it by saponifying the

3- [4- (Fluorenyl- (9) -acetamido-Biethyl) -phenyl] -propionic acid

Mp. 165-165 ⁰ C (purified over the potassium salt)

6. By conveying the 3- [4- (2-Ajninopropyl) -phenyl] -propionBaeureaethyleoter-hydrochlorido (Mp. 115-117 ° C) with fluorenyl (9) acetyl chloride the

5- <4- [2- (Fluorenyl- (9) -acetamido) -propyl] -phenyl> -propionic acid ethyl ester (c

and from it by saponifying the

5- <4- [2- (Fluorenyl- (9) -acetamido) -propyl] -phenyl) -propionic acid

Mp. 173-1-4 ° C (from toluene)

709881/0465

7 through TTmöetzamg doe 4- (2-Amino-ethyl) ~ zimtBaeuroaethyleuterhydrochloridc (mp. 218-220 ⁰ C) -acctylchlorid with Pluorcnyl- (9) the

. 4-Γ 2- (Fl-uorenyI- (9) -acetamido) -aethyll-cinnamon aeuroaGthyloat er mp. 160-162 ° C (aUB methylene chloride)

do it through Yerseifen die

ft-f2- (fluoro- enyl- (9) -acetamido) -aethyll-cinnamic acid m.p. 275-276 ^o C (from glacial acetic acid)

8. by UmoetEvung the α-methyl-4- (2-arainoaethyl) ~ cinnamon-daeureaethyl-Goter-hydrochloride (mp. 27O ^e C): with fluorenyl- (9) -acGtylchlorid den

α-Methyl-4- [2- (fluorenyl- (9) -acetamido) -aethyl] -cinnamic acid ethyl ester

Mp. 157-159 ° C (from xylene)

and from it through Terseifen the

g-Ethyl-4-f 2- (fluorenyl- (9) -acetamido) -aethyü1-cinnamic acid, melting point 223-226 ° C (from 70 56% kethanol)

9 by decomposition of the 2-methoxy-4- (2-aminoaethyl) -TDenzoenaeurcaethylostor-hydrochloride (p. 86-08 ⁰ C)

a) with fluorenyl- {9) -acetylchloride the

2-Methoxy-4- [2 ~ (fluorenyl- (9) -acetamido) -aethyl] - "ethyl benzoate (oil )

tmd from it by saponifying the

2-Hethoxy-4 ~ r2- (fluorenyl- (9) -acetamido) -aethyll-honzoic acid

. Mp 164-168OC

b) with 3-methoxy-fluorenyl- (9) -acetyl chloride the

2-Methoxy-4- [2- (3- ^ri iekhoxy-fluorenyl- (9) -acetamido) -aethyl] - Tjengoegoure-ethyl ester (oeli, ^)

and from it by saponifying the

2-methoxy-4- [2- (3-nethoxy-fluorenyl- (9) -acetamido) -aethyl] - ΐι enz ο es ae

Mp. 143-147 ^O C (from toluene)

10. by reacting the 5 ~ [4- (2-aminoethyl) phenyl] ~ valerian3aeureaethyltter hydrochlorideD (P.p. 148-152 ° c) with fluorenyl- (9) -acetyl chloride the

5- <4- [2- (Fluorenyl- (9) -acetamido) -aothyl] -phenyl> -valerian- BaeureaethyloBter _____

Mp. 80-92 ⁰ C (from isopropanol)

and from it by saponifying the

τ1- (9) -acetamido) -aethyll-phenyl ^ -valerian r; a euro m.p. 158-161 ° C (au3 ethyl acetate)

709881/0465

11. by reaction of the 2- [4- (2-Aminoaethyl) phenyl] propionsaeureaethyledter hydrochloride (Mp. 124-125 ° C) with fluorenyl (9) acetyl chloride the

2- ^ 4- [2-Fluorenyl- (9) -acetamido) -aethyl] -phenyl ^ -propionsaeiire ethyl s ter (oelip;) ~ __

and from it by saponifying the

2- ^ 4- [2- (fluorenyl- (9) -acetamido) -aethylj-phenyl ^ -propionic acid

P.p. 127 - 128 ° C (after sintering at 75 ° C) from isopropanol.

12. by reaction of the 7- [4- (2-Amivioaethyl) -pheiiyl] -heptansaeureaethylesterhydrochlorids (? p. 155-138 ° c) with fluorenyl- (9) -acetyl chloride the

7 - <(4- [2- (l'luorenyl- (9) -acetaraido) -aethyl] -phynyl) -hepbanoic acid- j aetbyl ester (oelir :) ■

and that \ is by saponifying the
7- <4- [2 - (? Luorenyl- (9) -acetaaido-ethyl] -phenyl> -heptanoic acid

Mp. 176-179 ^O C (from ethanol)

70988 1/0465

} i ' 2623752

example

4- (2- [3- (Fluorenyl- (9) -propionamido] -aethyl) -benzoic acid

To 1.5 g of 4- (2-aminoethyl) benzoic acid hydrochloride in 25.2 ml of 1 η sodium hydroxide solution are added at 0 ⁰ C was added dropwise a solution of 3-Fluorcnyl- (9) -propionyl chloride (prepared from 1.7 g of 3-i-Fluorenyl- (9) -propionic acid and thionyl chloride) in 12 ml of methylene chloride. The mixture is stirred first for ¹ hour under _Z2 Ei3ku.eh.lung and then 2 hours at room temperature. The layers are then separated, the aqueous-alkaline phase is washed again with methylene chloride and the free carboxylic acid is precipitated by acidification with diluted hydrochloric acid. It is saxified and recrystallized from ethane oil.
Yield 1.6 g (= 58.1 $ of theory) j mp 219-221 ° C

You get in analogue white

by reacting 4- (2-Aminoaethyl) -benzoesaexire hydrochloride with Fluorenyl- (9) -acetyl chloride the-

a) 4 ~ r2- (fluorenyl (9) acetamido) -aethyl1-benzoic acid mp. 248-250 ⁰ C (from ethanol)

• A

70988 1/0465

example

3- <4- [2- (Thioxanthenyl ~ (9) -acetamido) -aethyl] -phGnyl> -propionic acid

4.0 g of thioxanthenyl (9) acetic acid and 4.0 g of 3- [4- (2 »aminoethyl) - · phenyl / propionic acid ethyl ester hydrochloride were suspended in 20 ml of methylene chloride. For this purpose, while cooling to -15 ⁹ C, initially 1.5 ml of phosphorus oxide trichloride are added, then 6.4 ml of triethylamine are slowly added while stirring. It is stirred for one hour at -10 ° C and one hour at room temperature. The methylene chloride layer is then separated off and shaken off with 2 η hydrochloric acid and then with 2 η sodium hydroxide solution. The organic phase is dried and concentrated. The residue is 3- £ 4- [2- (thio ~ xanthenyl- (9 ^ -acetamido) -aethyl ] -phenyl ^ -propionnaeiirea-ethyl ester with a melting point of 122-127 ° C.
Yield 6.0 g (= 83.4 $ of theory)

6 g of 3 ~ <A -[2-(Thioxanthenyl-(9)-acetamido)-aethyl] -phenyl> -propionic acid ethyl ester are refluxed for 2 hours in a solution of 3 g of potassium hydroxide in 50 ml of ethanol. Then loosen and suck off the precipitated potassium salt, wash with ethanol and dissolve it in water. Acidification with dilute hydrochloric acid gives the free carboxylic acid, which is recrystallized from ethylene chloride.
Yield 3.3 S ( "56" 2 ^ theory) j mp. 188-189 ⁰ C.

You get in analogue Veioe

1. by reaction of 4- (2-aminoethyl) -bonzoesaeureaethyleBter- ' hydrochloride with the corresponding carboxylic acids the following compounds

709881/046 5

a) 4- [2- (6, ll-Dihydrodi "benzo ['b, e] thiepinylidene- (ll) -acetamido) ethyli-benzoc-saexireaethylcter (oily)

and from it by saponifying the

4- [2- (6, ll-dihydrodibenzo [b, e] thiepinylidene- (ll) -acetamido) ·

aethyl ~ j-benzoic acid

Pp. 187-189 ⁰ C (from 2-nitropropane)

b) 4- ^ 2- [3- (6, ll-Mhydrodibenz [b, e] oxepinyl- (ll)) -propionamido] - aethyl ^ -benzoic acid ethyl ester (oelift) '

and then by saponifying the 7th

4- ^ 2- [J- (6, ll-dihydrodibenz [b, eJoxepinyl- (11)) -propionamido] ~ ethyl ^ -benzoic acid ]

Mp. 55 ° C (after heating in diluted soda solution, treat with activated charcoal and precipitates with diluted sazoic acid)

2. through rewetting of the 3- [4- (2-Aminoaothy? -) - phenyl] -propioncaeureaothyleßter-hydrochlorida with the corresponding Carbonic acids the following compounds

_a ) 3_ £ 4_ [2- (9,10-Mhydroanthracene-3-carboxamido) -aethyl] -phenyl ^ - propionic acid ethyl ether (oily) ;

and then by saponifying the

3 _ <; 4_ [2- (9,10-I) ihydroanthracene -. "9-carboxaniido) -aethyl] -phenyl>propionsaeux-e" . ,, ____

Mp. 148-149 ⁰ C (from 80 ^ sodium ethanol)

7-709S81 / 0465

5 - <* 4- [2- (Pluorenyl- (9) -carboxamido) -aethyl] -phenyl> -propionic acid ethyl ester

Mp. 138-140 ⁰ C (from 80 ^ -igem ethanol) and darp / uo by saponifying the

3- <4 ~ [2- (Fluorenyl- (9) -car "boxamido) -aethyl] -phynyl> -propionic acid

Mp. 2O5-2O6 ° C (from isopropanol)

c) 3- <4- [2- (3-Methoxy-fluorenyl- (9) -acetamido) -aethyl] -phenyl> propionic acid ethyl ester (Pel) -_ -_ ^

and from it by saponifying the

3- <4- [2- (3-M ^e thoxy-fluorenyl- (9) -acetamido) -ethyl] -phenyl> propionsaeur e -

Mp. 107-18B ⁰ C (from ethanol)

3 ~ <"4- <2- [3- (fluorenylidene- (9) ·) -propionamidc] ~ ethyl> ~ phenyl> propionsaetireaethyleater (Pel) .

and from it through Veroeifen the

3- <4- <2- [3- (fluorenylidene- (9)) -propionamido] -aethyl>-phenyl> propionic acid

Mp. 236-238 ^o C (from 80 5 ^ -igem isopropanol)

'/' 709881 / 046B

^e ) 5- <4- [2- (6, ll ~ _ihyd_o & ibenz [_, e] thiepinyl- (ll) -acetamido) -ethyl! -phenyl } -propionsacureaethylester (Pel)

and from it by saponifying the

3- <4- [2- (6, II-dihydroxodi "benz [h, e] thiepinyl- (II) -acetamido) .ethyl 1-phenylV-propionic acid

Mp. 154-155 ° C (from toluene)

3. by Uniüctzunc dos 4- (2-Arainoaethyl) -2-niethoxy-benzoeßaoureaothyleßcr-hydrochlorida rait [1-methoxy-fluorenyl- (9)] -gsoigic acid the

2-Hethoxy-4- [2- (l-raethoxy-fluoro-nyl- (9) -acetamido) -aethyl] - "benzoenaGurcaethyleater (Oftl)

and by saponifying the ~ ■ '

2-Methoxy-4- [2- (1-methoxry-fluorenyl- (9) -acetamido) -aethyl] · foenzoic acid

Pp. 155-157 ^O C (from isopropanol)

709881 / 046S

Example 4

4 ~ [2- (2-methoxy-6, ll-dihydrodibenz [b, e] oxopinylidene- (11) -acetamido) - aethyli-benzoesaetire '

To 2.5 g of 4- (2 ~ aminoethyl) -benzoeGaeureaethylester hydrochloride in 20 ml of absolute pyridine is added dropwise at 0 ⁰ C sine solution of 0.75 g of phosphorus trichloride in 10 ml of absolute pyridine, stirred for 15 minutes at O ⁰ C and 30 several minutes at 20 ⁰ C and then 2.82 g of 2-methoxy-6, ll-dihydrodibenz [b, e] oxepinyliden- (II) to -es3igsaeure. The mixture is left to stir overnight, then poured into ice-cold hydrochloric acid, extracted several times with methylene chloride, deacidified the organic phase with sodium hydrogen carbonate solution, dried and concentrated. 3.4 g of the ester are obtained in oily form. These 3.4 g are saponified with 25 ml of 2 η sodium hydroxide solution and 25 ml of ethanol for 30 minutes on a water bath. The ethanol is then drawn off, the aqueous solution extracted with methylene chloride and acidified. The separated oil is taken up in methylene chloride, dried and completely concentrated. The residue is circumscribed from ethyl acetate.
Yield 2.1 g (= 49 $ of theory) j. Mp. 191-193 ° C.

One gets in an analogous way

by reacting the 4- (2-aminoethyl) benzoic acid ethyl ester • hydrochloride with 6, ll-dihydrodibenz [b, e] oxepinylidene (ll) acetic acid the'

a) 4- [2- (6, II-dihydrodibenz [b, e] oxepinylidene- (II) -acetamido) -aethyli-benzoeaeureaethyleoter (Pol) .

xmd from it by Terseifen the

4- [2- (6, ll-dihydrodibenz [b, e] oxepinylidene- (ll) -acetamido) - aethyll-benzoic acid ^ ______

Mp. 247-250 ^o C (from 50 $ methanol)

709S81 / 0A6S

Example 5

5- <4- [2- (fluorenyl- (9) -acetamido) -ethyl] -phenyl> -2-methyl propionaaeure

51 5 ~ ß a Kethyl-4- [2 ~ (fluorenyl (9) -acetamido) -ethyl] ~ cinnamic acid are hydrogenated in 100 ml of glacial acetic acid and 2 ml of water in the presence of palladium »charcoal under atmospheric pressure. After the uptake of 1 mol of hydrogen per substance used, the reaction is ended; after the catalyst has been filtered off with suction, the solution is concentrated and water is added to the residue. The precipitating ? - <4-T ² ~ (fluorenyl- (9) -acetamido) -aethyl "| -phenyl> -2-ynethyl-propionic acid is sucked off Tina, rait Vasser rewashed. The substance is immediately pure. Yield 4> 8 g (= 90 ^ of theory) j mp 147-15O ° C.

One gets in an analogous way

a) from 4- [2- (fluorenyl- (9) -acetamido) -aethyl] -cinnamic acid the

3- <4- [2- (Fluorenyl- (9) -acetamido) -aethyl] -phenyl> -propionic acid

Mp. 218-219 ° C (from ethyl acetate)

b) from 5- <4- [2- (fluorenylidene- (9) -acetamido) -aethyl] -phenyl> propionic acid also the

3- [4- [2- (Fluorenyl- (9) -acetamido) -aethyl] -phenyl) -propionic acid

Mp. 218-219 ° (from ethyl acetate)

· / · 709881/0465

Example 6

^ .- r2- (Flii.orenyl- (9) -acetamido) -aethyl1-zimtoacure

To 4.2 g of 4- [2- (fluorenyl ~ (9) -acetaiiiido) -aethyl] -benzaldehyde (melting point 140-143 ° C.) and 4 »0 g of phosphonofigic acid triethylether in 24 ml of absolute dimethylformamide is added under pressure A mixture of 3.6 ml of 30% sodium methylate solution and 36 ml of methanol was added dropwise. Then stir for a further 2 hours at room temperature, increase with ice and water and adjust to pH = 6 with acetic acid. The 4-f2- (fluorenyl- (9 ) -acet ~ ami.do) -aethyl1-cinnamic acid ethyl ester formed is filtered off with suction and washed with water.
Yield 3.6 g («70 ^ of theory) | Mp. 162-165 ° C.

This ester (3.6 g) is refluxed with 2.5 g of potassium hydroxide in 35 ml of ethanol for 2 hours. After cooling, the precipitated potassium salt is filtered off with suction, washed with ethanol and dissolved in water. The solution is treated with activated charcoal and then acidified with diluted hydrochloric acid. The free carboxylic acid is filtered off with suction and recrystallized from glacial acetic acid. Yield 2.2 g («65 % of theory) _} mp.

In an analogous Veise using 2-PhoBphonopropionsaeuretriaethylester (boiling point _1B : 152-156 ° c) the

cc-Mothyl-4-Γ 2- (fluorenyl- (9) -acetamido) -aethyll-cinnamon acid ethyl ester, melting point 157-159 ^O C (from xylene)

and from it by saponifying the

cc-methyl-4-r2- (flucrenyl- (9) -acetamido) -ethyl '|. -ziintsaeure mp 223-226 ^o C (from 70 jk-methanol)

709881/0465 • I '

Example 7

4-f2- (Pl \ xorcnyl- (9) -acetamido) -aothyll- "benzoic acid

4.0 g of sodium dichromate dihydrate are added to the solution of 3.6 g of 4- [2- (pluorenyl- (9) -acetamido) -aethyl] benzyl alcohol (melting point 176-178 ° C.) in 50 ml of glacial acetic acid, and the mixture is stirred for 8 hours at 50 ⁰ G. the glacial acetic acid distilled off vird on a rotary evaporator, taken up with the Rueckotand V.'asser and dilute sodium hydroxide solution and some unreacted starting material was removed by extraction with ethyl acetate. Then you acidify with diluted hydrochloric acid and get the free carboxylic acid, which is recrystallized from ethanol.
Yield 2.1 g (= 56 $ of theory) j mp.

In an analogous manner, using 4- [2- (Fluore_yl- (9) -acetaraidoj-aethylj-benzaldehyde) is obtained (M.p. 140-143 ° C) as starting material also 4- [2- (fluorenyl- (9) -acetamido) -aethyl] -benzoic acid.

Example 8

(l-Phenaethyl-bigua-nid) -3- ^ 4- [2- (fluorenyl- (9) -acetamido) -aethyl] - phcnyjV-propionate (does not get KII-Uiacier)

4i0 S 5- ^ 4- [2- (pluorenyl- (9) -acetamido) -aethyl] -phenylV-propionic acid are dissolved in 100 ml 0.1 η sodium hydroxide solution .. In addition, a solution of 2.42 g l- Phenaethylbiguanide hydrochloride in 40 ml of water. Both solutions are mixed at room temperature; the desired salt fails. v liach one hour, and the product ill be sucked off, washed with water and mehrnals in Yakuum oven at 70 ⁰ C dried. 2.1 g (= 35% of theory) (1-phenaethyl-biguanide) ~ 3- ^ 4- [2- (fluorenyl- (9) -acetamido) -aethyl] -phenyl) ~ propionate with a melting point are obtained 1O4-1O6 ° C. More substance can be obtained by concentrating the mother liquor.

709881/0465

Claims (4)

Claims ι 1.! Carboxylic acid derivatives of the general formula I A V-CO-NH-Y- -X-COOH Vl / R, (D, in the A is a valence line or one of the groups -CH ₂ -, -CH = CII-, -0-, -CH ₂ -O-, -S-, -CH ₂ -S-, -CH ₂ -CK ₂ -, V is a straight-chain or branched, saturated or unsaturated trivalent hydrocarbon radical with 1-4 carbon atoms, R ₁ and R _{2 can be} identical or different and are hydrogen, hydroxyl, alkyl, alkoxy or halogen, R _{3 is} hydrogen _f hydroxy or an alkoxy group, 709881 Y o an optionally branched lower alkylene group with 1-3 carbon atoms, X a valence bar, a straight or branched chain, saturated or unsaturated alkylene chain with 1-6 carbon atoms mean and their physiologically harmless salts, esters and amides. 2. Process for the preparation of carboxylic acid derivatives of the general Formula I. A V-CO-HH-Y- ^ ^ -X-COOII (l), in the A is a line or one of the groups -CH ₂ -, -CH ₂ -CK ₂ -, -CH = CH-, -0-, -CH ₂ -O-, -S-, -CH ₂ -S-, a straight-chain or branched, saturated or unsaturated trivalent hydrocarbon radical with 1-4 carbon atoms, R ₁ and R _{2 can be} identical or different and are hydrogen, hydroxy, alkyl, alkoxy radicals or halogen, R _{3 is} hydrogen, hydroxy or an alkoxy group, 7ÖS881 / 046S Y has an optionally branched lower alkylene group 1-5 carbon atoms ι X a valence stroke, a straight-chain or branched one, mean saturated or unsaturated alkylene chain with 1-6 carbon atoms as well as their physiologically harmless salts, esters and amides, characterized in that either α) an amino-carboxylic acid of the general formula II x-COOH (II), in the Y, X and E _{3 have} the meanings listed above, or their acid derivatives, _, reacts with a reactive acid derivative of the acid T-COOH, viobei T for the trioyclic system V- of the formula I, in which A, V, R, and R _{2 have} the meanings given above, or b) a compound of the general formula III T-CO-KII- Υ-ά Λ-Χ-Β. (Ill), K ₃ in the T, Yi K ₃ and X have the meanings given above and B represents a radical which can be converted oxidatively into the carboxyl group, oxidized or c) in the event that X is a straight-chain or branched, saturated or unsaturated alkylene chain with 1-6 carbon atoms means "a compound of the general Formula IV T-CO-NK-Y- ^ Λ-Z'-G-Z-COOR (iV), in vrelcher. T, R ₃ and Y have the meanings given above, Z and Z ^{1 can be} identical or different and have a valence stroke, a straight-chain or branched, saturated or unsaturated alkylene chain with 1-5 carbon atoms, R is hydrogen or an alkyl group and G denote the -C group or the -CH group, Il 0 ί where L represents the hydroxyl group or halogen, reduced, or 709881/0465 J. ~ f ~ 2628752 d) more fix in the case that X is a straight-chain or branched, saturated or unsaturated alkylene chain with 2-6 carbon atoms, a compound of the general formula V T-CO-ITH-Y- / A-K-C = O. (V), in the T _t R ₃ and Y have the meanings given above, M represent hydrogen or lower alkyl with 1-4 carbon atoms, and K represent a valence stroke or a straight-chain or branched, saturated or unsaturated alkylene chain with 1-4 carbon atoms, with a reactive methylene component of the general formula VI E ₂ C -, (VI), in the R 'is hydrogen, alkali metal _f lower alkyl or an acyl group and • Q represents hydrogen, lower alkyl with 1-4 carbon atoms or an activating group, such as the Mitril group or one of the radicals -COOR ¹ or -PO (OR) ₂ , in which IV and R are as defined above, reacted, the resulting unsaturated compound being given j if subsequently saponified, decarboxylated or hydrogenated, or 709881/046 p e) in the event that X is straight or branched, saturated or is an unsaturated alkylene chain with 1-6 carbon atoms, a derivative of a carboxylic acid of the general formula VII T-CO-ITII-Y- / Vx'-COOH (VII), in the T, K ₃ and Y have the meanings given above and X ^{1 represents} a radical smaller than X by one methylene group, reacts with diazomethane according to "Arndt-Eistert", or f) in the event that X in the general formula I a straight chain, saturated alkylene chain with 1-4 carbon ft represents atoms, a ketone of the general formula VIII T-CO-NH-Y- / λ-CU (VIII), in dor T ₁ K ₃ and Y have the meanings given above and U represents an alkyl group having 1-4 carbon atoms, under the conditions of an optionally modified "V / illgerodt-Kindler synthesis", or .A 709881/046 in the event that X is a straight-chain or branched, saturated or unsaturated -alkylene chain with 2-6 carbon atoms means a halogen compound of the general formula IX M.
T-CO-KH-Y-4. / VK-CH-HaI (iX), in the T, E ₃ , Y, K "and K have the meanings given above and Hal represents a halogen with a reactive methylene component of the general formula X. COOR ₅ COV / past R _{4 is} hydrogen or lower alkyl with 1-4 carbon atoms, B _{5 is} lower alkyl, Me is an alkali or alkaline earth metal and V is OR ₅ or the methyl group, ■ converts, saponifies and optionally decarboxylates, " and then, if appropriate, convert the compounds of general formula I obtained into other compounds of general Formula I converted and an acid derivative obtained from the general Formula I optionally converts into the free acid or a resulting free acid of the general formula I, if desired esterified, converted into an amide or into a physiologically acceptable salt. ./.709881/046S 3. Use of carboxylic acid derivatives of the general formula I for the preparation of drugs with hypoglycemic and / or hypolipidemic effect. 4. Pharmaceutical preparations, characterized by a content on carboxylic acid derivatives of the general formula I. 709881/0465